Systemic enzyme therapy with trypsin, bromelain and rutoside in the management of arthritis: an overview
DOI:
https://doi.org/10.18203/issn.2455-4510.IntJResOrthop20213392Keywords:
Proteolytic enzymes, Cytokines, Anti-inflammatory, Osteoarthritis, Rheumatoid arthritisAbstract
Chronic arthritis, including osteoarthritis and rheumatoid arthritis, is a growing major public health problem leading to disability and reduced quality of life. Analgesic and anti-inflammatory drugs form the mainstay of treatment for chronic arthritis. The protracted use of the conventional medications for their management is fraught with shortcomings, including safety concerns. Proteolytic enzymes and antioxidant combinations have been used empirically, since ages, in many of these conditions. There is a growing body of evidence indicating the beneficial effects exerted by the individual ingredients and their combinations on the pathophysiology of arthritis. The analgesic, anti-inflammatory, anti-edematous, anti-thrombotic and anti-oxidant properties of these substances have been demonstrated in multiple in vitro and animal models. Furthermore, the therapeutic use of proteolytic enzyme-antioxidant combination is also supported by clinical trials in arthritis and related disorders. Such studies have mostly been carried out on preparations consisting of combinations of trypsin, bromelain and rutoside. The results of various studies (placebo-controlled and comparisons with nonsteroidal anti-inflammatory (NSAIDs) drugs) in patients with arthritis suggest that oral therapy with such enzyme-antioxidant combination produces improvement in all major clinical parameters like swelling, pain and joint stiffness and have comparable efficacy to NSAIDs. Some clinical studies also evaluated their effect on biochemical markers like cytokines, interferons and prostaglandins and reported remarkable improvements. The overall data also indicates that the tolerability of the enzyme-antioxidant combination is better than conventional therapies.
References
Mitra S. Arthritis: classifications, nature and cause-a review. Am J Biopharmacol Biochem Life Sci. 2013;2(3):1-25.
Senthelal S, Li J, Goyal A, Bansal P, Thomas M. Arthritis. Treasure Island (FL): StatPearls Publishing; 2020.
Jayachandran S, Khobre P. Efficacy of bromelain along with trypsin, rutoside trihydrate enzymes and diclofenac sodium combination therapy for the treatment of TMJ osteoarthritis-a randomised clinical trial. J Clin Diagn Res. 2017;11(6):9.
Bolten W, Glade M, Raum S, Ritz B. The safety and efficacy of an enzyme combination in managing knee osteoarthritis pain in adults: a randomized, double-blind, placebo-controlled trial. Arthritis. 2015;2015:1-7.
Kasemsuk T, Saengpetch N, Sibmooh N, Unchern S. Improved WOMAC score following 16-week treatment with bromelain for knee osteoarthritis. Clin Rheumatol. 2016;35(10):2531-40.
Kloppenburg M, Berenbaum F. Osteoarthritis year in review 2019: epidemiology and therapy. Osteoarthritis Cartilage. 2020;28(3):242-8.
Cui A, Li H, Wang D, Zhong J, Chen Y, Lu H. Global, regional prevalence, incidence and risk factors of knee osteoarthritis in population-based studies. E Clin Med. 2020;29:100587.
Bullock J, Rizvi S, Saleh A, Ahmed S, Do D, Ansari R, et al. Rheumatoid arthritis: a brief overview of the treatment. Med Princip Pract. 2018;27(6):501-7.
Lucena F, Foletto V, Mascarin L, Tonussi C. Analgesic and anti-edematogenic effects of oral trypsin were abolished after subdiaphragmatic vagotomy and spinal monoaminergic inhibition in rats. Life Sci. 2016;166:60-5.
Handa R, Rao U, Lewis J, Rambhad G, Shiff S, Ghia C. Literature review of rheumatoid arthritis in India. Int J Rheum Dis. 2016;19(5):440-51.
Wu Y, Goh E, Wang D, Ma S. Novel treatments for osteoarthritis: an update. Open Access Rheumatology: Research and Reviews. 2018;10:135-40.
Gupta R, Malhotra A, Malhotra P. Study of prescription pattern of drugs used in the treatment of osteoarthritis in a tertiary care teaching hospital: an observational study. Int J Res Med Sci. 2018;6(3):985.
Marcum Z, Hanlon J. Recognizing the risks of chronic nonsteroidal anti-inflammatory drug use in older adults. Ann Longterm Care. 2010;18(9):24-7.
Machado-Duque M, Ramírez-Valencia D, Murillo-Muñoz M, Machado-Alba J. Trends in opioid use in a cohort of patients with rheumatoid arthritis. Pain Res Manag. 2020;2020:3891436.
Bird P, Griffiths H, Littlejohn G. Methotrexate in rheumatoid arthritis: efficacy and safety. J Pharmacovigil. 2014;02(2):1-4.
He Y, Li Z, Alexander P, Ocasio-Nieves B, Yocum L, Lin H, et al. Pathogenesis of osteoarthritis: risk factors, regulatory pathways in chondrocytes, and experimental models. Biology. 2020;9(8):194.
Johns Hopkins Arthritis Center. Fact sheet: Osteoarthritis: Pathophysiology. Available at: https://www.hopkinsarthritis.org/arthritis-info/osteoarthritis/oa-pathophysiology/. Accessed on 14 May 2021.
Kim J, Yoo J, Kim H. Therapeutics in osteoarthritis based on an understanding of its molecular pathogenesis. Int J Mol Sci. 2018;19(3):674.
Veale D, Orr C, Fearon U. Cellular and molecular perspectives in rheumatoid arthritis. Semin Immunopathol. 2017;39(4):343-54.
Guardia T, Rotelli A, Juarez A, Pelzer L. Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat. Farmaco. 2001;56(9):683-7.
Sun C, Wei J, Bi L. Rutin attenuates oxidative stress and proinflammatory cytokine level in adjuvant induced rheumatoid arthritis via inhibition of NF-κB. Pharmacology. 2017;100(1-2):40-9.
Prasad R, Prasad S. A review on the chemistry and biological properties of Rutin, a promising nutraceutical agent. Asian J Pharm Pharmacol. 2019;5(1):1-20.
Ostrakhovitch E, Afanas’ev I. Oxidative stress in rheumatoid arthritis leukocytes: suppression by rutin and other antioxidants and chelators. Biochem Pharmacol .2001;62(6):743-6.
Lorkowski G. Gastrointestinal absorption and biological activities of serine and cysteine proteases of animal and plant origin: review on absorption of serine and cysteine proteases. Int J Physiol Pathophysiol Pharmacol. 2012;4(1):10-27.
Lehmann P. Immunomodulation by proteolytic enzymes. Nephrol Dial Transplant. 1996;11(6):952-5.
Brien S, Lewith G, Walker A, Middleton R, Prescott P, Bundy R. Bromelain as an adjunctive treatment for moderate-to-severe osteoarthritis of the knee: a randomized placebo-controlled pilot study. QJM. 2006;99(12):841-50.
Walker A, Bundy R, Hicks S, Middleton R. Bromelain reduces mild acute knee pain and improves well-being in a dose-dependent fashion in an open study of otherwise healthy adults. Phytomed. 2002;9(8):681-6.
Rathnavelu V, Alitheen N, Sohila S, Kanagesan S, Ramesh R. Potential role of bromelain in clinical and therapeutic applications. Biomedical Rep. 2016;5(3):283-8.
Gul A, Kunwar B, Mazhar M, Faizi S, Ahmed D, Shah M, et al. Rutin and rutin-conjugated gold nanoparticles ameliorate collagen-induced arthritis in rats through inhibition of NF-κB and iNOS activation. Int Immunopharmacol. 2018;59:310-7.
Mynott T, Ladhams A, Scarmato P, Engwerda C. Bromelain, from pineapple stems, proteolytically blocks activation of extracellular regulated kinase-2 in T cells. J Immunol. 1999;163(5):2568-75.
Secor E, Singh A, Guernsey L, McNamara J, Zhan L, Maulik N, et al. Bromelain treatment reduces CD25 expression on activated CD4+ T cells in vitro. Int Immunopharmacol. 2009;9(3):340-6.
Fitzhugh D, Shan S, Dewhirst M, Hale L. Bromelain treatment decreases neutrophil migration to sites of inflammation. Clin Immunol. 2008;128(1):66-74.
Kumakura S, Yamashita M, Tsurufuji S. Effect of bromelain on kaolin-induced inflammation in rats. Eur J Pharmacol. 1988;150(3):295-301.
Gaspani L, Limiroli E, Ferrario P, Bianchi M. In vivo and in vitro effects of bromelain on PGE2 and SP concentrations in the inflammatory exudate in rats. Pharmacology. 2002;65(2):83-6.
Sahbaz A, Aynioglu O, Isik H, Ozmen U, Cengil O, Gun B, et al. Bromelain: a natural proteolytic for intra-abdominal adhesion prevention. Int J Surg. 2015;14:7-11.
Sharma M, Chaudhary D. Exploration of bromelain laden nanostructured lipid carriers: an oral platform for bromelain delivery in rheumatoid arthritis management. Int J Pharm. 2021;594:120176.
White M, Gomer R. Trypsin, Tryptase, and Thrombin Polarize Macrophages towards a Pro-Fibrotic M2a Phenotype. PLoS One. 2015;10(9):0138748.
Umar S, Mishra N, Pal K, Sajad M, Ansari M, Ahmad S, et al. Protective effect of rutin in attenuation of collagen-induced arthritis in Wistar rat by inhibiting inflammation and oxidative stress. Indian J Rheumatol. 2012;7(4):191-8.
Ferraz C, Carvalho T, Manchope M, Artero N, Rasquel-Oliveira F, Fattori V, et al. Therapeutic potential of flavonoids in pain and inflammation: mechanisms of action, pre-clinical and clinical data, and pharmaceutical development. Molecules. 2020;25(3):762.
Kauss T, Moynet D, Rambert J, Al-Kharrat A, Brajot S, Thiolat D, et al. Rutoside decreases human macrophage-derived inflammatory mediators and improves clinical signs in adjuvant-induced arthritis. Arthritis Res Ther. 2008;10(1):19.
Sujitha B, Kripa K. Anti-arthritic and anti-inflammatory polyphenols from Caryota urens L.: a molecular docking analysis. Res J Pharm Technol. 2020;13(9):4269-73.
Chintalacharuvu S, Urankar-Nagy N, Petersilge C, Abdul-Karim F, Emancipator S. Treatment of collagen induced arthritis by proteolytic enzymes: immunomodulatory and disease modifying effects. J Rheumatol. 2001;28(9):2049-59.
Rovenska E, Svik K, Stancikova M, Rovensky J. Inhibitory effect of enzyme therapy and combination therapy with cyclosporin A on collagen-induced arthritis. Clin Experiment Rheumatol. 2001;19(3):303-9.
Brien S, Lewith G, Walker A, Hicks S, Middleton D. Bromelain as a treatment for osteoarthritis: a review of clinical studies. Evid Based Complement Alt Med. 2004;1(3):251-7.
Leipner J, Iten F, Saller R. Therapy with proteolytic enzymes in rheumatic disorders. Bio Drugs. 2001;15(12):779-89.
Singer F, Oberleitner H. Drug therapy of activated arthrosis. On the effectiveness of an enzyme mixture versus diclofenac. Wiener Medizinische Wochenschrift. 1996;146(3):55-8.
Tilwe G, Beria S, Turakhia N, Daftary G, Schiess W. Efficacy and tolerability of oral enzyme therapy as compared to diclofenac in active osteoarthrosis of knee joint: an open randomized controlled clinical trial. JAPI. 2001;49:617-21.
Ueberall M, Mueller-Schwefe G, Wigand R, Essner U. Efficacy, tolerability, and safety of an oral enzyme combination vs diclofenac in osteoarthritis of the knee: results of an individual patient-level pooled reanalysis of data from six randomized controlled trials. J Pain Res. 2016;9:941-61.
Bai KS, Naik PS, Naik MAB, Riyaz N, Kushbu D. An observational study comparing the efficacy and tolerability of trypsin, bromelain, rutoside and zinc combination with diclofenac sodium in patients suffering from osteoarthritis knee attending orthopedic OPD, GGH, Anantapuramu. Int J Curr Adv Res. 2015;4(12):545-8.
Acharya T, Trivedi M, Mehta D, Chhaiya S, Gandhi S. A comparative study of effect on reducing pain, inflammation and side effect of combination of enzymes (bacterial proteases, papain, bromelain, vitamin C and rutin) versus conventional non-steroidal anti-inflammatory drugs (diclofenac) in patients of closed fracture lower end radius coming at orthopaedic department of a tertiary care hospital. Int J Basic Clin Pharmacol. 2016;5(3):1017.